ABSTRACT Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and is associated with a 5-fold increase in the risk of stroke, a 3-fold increase in the risk of heart failure, and a doubling in the risk of death. Once it occurs, AF is difficult to treat, and often requires therapies, such as systemic anticoagulation, that have serious adverse effects. Despite the obvious need for preventive therapies, no adequately powered trials of AF prevention have been conducted. Therefore, in this cost-efficient and innovative proposal, we propose to test in a randomized, double-blind, placebo-controlled setting whether inflammation inhibition prevents incident AF, reduces the duration of AF episodes, and improves the quality of life of patients with AF. To test this hypothesis, we propose to extend the ongoing Cardiovascular Inflammation Reduction Trial (CIRT), an ongoing, NIH-funded (U01 HL101422 and U01 HL101389) multi-center trial of low- dose methotrexate (15-20 mg per week) plus usual care versus usual care alone in the prevention of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death in patients with preexisting coronary artery disease and either type 2 diabetes or the metabolic syndrome. CIRT has randomized more than 4,000 patients out of a goal of 7,000 at more than 350 clinical sites in the United States and Canada. Our study will use rigorous detection and validation methods for both symptomatic and asymptomatic AF, including the use of a novel 10 to 14-day continuous ECG monitor in all CIRT participants, in order to test whether random allocation to inflammation inhibition with low dose methotrexate reduces the incidence and burden of AF in a population at high risk for the disorder. Subclinical inflammation is an important risk factor for the development of AF, appears to cause important structural and electrical changes in the atria, and leads to the initiation and propagation of atrial fibrillation. We believe that the ongoing CIRT trial offers a unique opportunity to test whether specifically inhibiting the underlying inflammatory pathways involved in AF pathogenesis may prevent the arrhythmia in a high-risk population. This cost-efficient and timely grant represents the first adequately powered trial for the primary prevention of AF.